Computational Insights into PB1-F2 Mediated Modulation of VDAC1: An Allosteric Mechanism in Mitochondrial Dysfunction

The influenza-encoded virulence factor PB1-F2 has been implicated in a mitochondrial dysfunction of host immune cells through its interaction with the Voltage-Dependent Anion Channel 1 (VDAC1). This protein is a key outer mitochondrial membrane channel involved in ion and metabolite transport. Despite their well-known association, the precise interaction sites between these proteins remain unclear. In the current study, we employed multireplica all-atom molecular dynamics (MD), steered MD simulations, and docking approaches to investigate their mode of interaction. Our results reveal a putative binding site for PB1-F2 on the VDAC1 channel, as residue E73 has been reported to have physiological relevance in VDAC1 function; this region was initially explored as a potential interaction site. Furthermore, simulations based on multiple replicas revealed allosteric effects on VDAC1, increasing the dynamics of pore-lining residues and indicating a shift toward a probable closure-like conformation. We identify a stable binding interface at a global energy minimum, where PB1-F2 interacts via electrostatic interactions with the N-terminal pore-lining residues of VDAC1, which was also validated by voltage-driven simulations. We observed that due to the positive charge of PB1-F2, its interaction with the VDAC1 pore did not significantly affect the ionic conductance or selectivity of the channel. These findings provide molecular insights into how PB1-F2 modulates the function of VDAC1, reinforcing its role in modifying the permeability and possibly apoptosis induction. Understanding this interaction at an atomic level may inform novel strategies to deal with influenza-encoded virulence-induced dysfunctions of immune cells.